Public health relevance: Disruptions in neurodevelopmental events are responsible for a wide range of diseases, including Autism, Fragile X, Lissencephaly, and Kallman's syndrome, that severely affect our society. Before we, as a medical community, can figure out how to treat these devestating disorders, we must first understand on a molecular and cellular level what events have gone wrong developmentally. This study explores the formation of the olfactory pathway as a model system to guide our understanding of critical principles in molecular and cellular development, including axon guidance, cell migration, and cellular differentiation. Only by gaining insight into these fundamental processes will we be able to make progress towards the treatment of neurodevelopmental disorders. Specifically, this proposal focuses on the development of the primary olfactory nerve pathway (ONP), which connects the olfactory sensory neurons (OSNs), which reside in the OE, to the olfactory bulb (OB). The formation of the ONP is comprised of a series of coordinated events that includes the differentiation of cells within the olfactory placode (OP), extension of olfactory sensory neuron (OSN) axons into the mesenchyme, and finally the approach of the axons to the presumptive olfactory bulb (pOB). Our goal is to understand the initial key events central to the proper formation of this pathway and the organization of the axons within the developing olfactory nerve pathway (ONP). Earlier studies noted neuron-like cells within the mesenchyme in close apposition to the OSN axons. Our working hypothesis is that these are OP derived pioneer neurons, which we have termed migrating olfactory placode cells (MOPCs), that contribute to a scaffold or framework utilized by the OSN axons as they establish the initial topography between the OE and OB. Specifically, we hypothesize that MOPCs act as a substrate for the OSN axons during the formation of the ONP and its approach to the pOB. This hypothesis is based on the following: First, throughout the CNS there is evidence for guidepost neurons infiuencing the formation of axon pathways. Second, our preliminary data demonstrate that OSN axons emerge from the OP after the initial transition of MOPCs into the mesenchyme. Third, some MOPCs express odor receptors (ORs) which have been implicated in OSN axon guidance (1). These data suggest that the positioning of the MOPCs is not stochastic but, rather, occurs within a molecularly defined topography that underlies the formation of the olfactory nerve and OSN axon targeting. Our overarching goal is a characterization of the MOPCs and the role(s) they may play in establishing the interface between the olfactory epithelium and pOB.